April 16, 2007 — The US Centers for Disease Control and Prevention (CDC) have issued new treatment recommendations for gonorrhea, which are published in the April 13 issue of the Morbidity and Mortality Weekly Report. The new guidelines recommending cephalosporin treatment are in response to gonorrhea resistance to fluoroquinolones, which is now widespread in the United States among heterosexuals and men who have sex with men.
“Gonorrhea is the second most commonly reported infectious disease in the US, with about 340,000 cases reported in 2005,” John M. Douglas, Jr., MD, Director of the Division of Sexually Transmitted Diseases Prevention (DSTD), National Center for HIV/AIDS, Viral Hepatitis, STD [sexually transmitted disease], and TB Prevention (NCHHSTP), said in a CDC teleconference. “Like most STDs, gonorrhea is underdiagnosed and underreported, and we estimate that about twice that number of people were affected. We’ve made substantial progress in reducing the burden of gonorrhea over the years as a result of efforts to prevent, detect and effectively treat the disease.”
Rising rates of gonorrhea resistance to fluoroquinolones were first noted in Hawaii and California, leading the CDC to recommend in 2000 and in 2002, respectively, that fluoroquinolones not be used to treat gonorrhea infections in these states. In 2004, rising rates of gonorrhea resistance to fluoroquinolones in men who have sex with men led the CDC to recommend against using fluoroquinolones in this group.
“Part of our success in controlling this disease has been our ability to treat the changing organism itself,” Dr. Douglas says. “Gonorrhea has proven to be quite efficient at navigating around the drugs we use to combat it, with resistance first to penicillin, then tetracycline, then, most recently, to fluoroquinolones…. We want a recommended treatment to cure 95% or more of all gonorrhea infections, [and] we have reached a level of resistance that threatens our ability to control the disease across populations.”
Data from CDC’s Gonococcal Isolate Surveillance Project (GISP) in 26 US cities showed that in the first half of 2006, 6.7% of gonorrhea cases in heterosexual men were fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG), an 11-fold increase from 0.6% in 2001, and well above 5%, the recognized threshold for changing treatment recommendations.
“As a result of these increases in fluoroquinolone resistance throughout the country, CDC is no longer recommending that fluoroquinolones be used to treat gonorrhea anywhere in the U.S.,” Dr. Douglas says. “These recommendations are critical to preserve the progress we’ve made in controlling gonorrhea, one of the nation’s most common STDs.”
The overall proportion of gonorrhea cases that were QRNG increased from less than 1% in 2001 to 13.3% in the first half of 2006, with dramatic increases from 2004 to 2006 in Philadelphia (1.2% – 26.6%) and Miami (2.1% – 15.3%). QRNG also continued to rise among men who have sex with men, from 1.6% in 2001 to 38% in the first half of 2006.
“We do not have the full data yet from the last half of 2006,” Hillard S. Weinstock, MD, MPH, Medical Epidemiologist, DSTD, NCHHSTP, said in the teleconference. “However, given the trends we have observed over the last several years, we expect that the percentage of fluoroquinolone-resistant cases will go up in the second half of 2006.”
Therefore, the CDC no longer recommends fluoroquinolone antibiotics (ciprofloxacin, ofloxacin, and levofloxacin) for treatment of gonorrhea in the United States. Because gonorrhea resistance to penicillin, sulfa drugs, and tetracycline is already widespread, this limits available options for gonorrhea treatment to drugs in the cephalosporin class. The United Kingdom preceded the United States by about 3 to 4 years in its recommendation to switch from fluoroquinolones to cephalosporins in gonorrhea treatment.
“There is an urgent need for new, effective medicines to treat gonorrhea,” Kevin Fenton, MD, Director of CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, said in a news release. “We are running out of options to treat this serious disease. Increased vigilance in monitoring for resistance to all available drugs is essential.”
Although significant resistance to cephalosporins has not been reported thus far, CDC is collaborating with state and local health departments to detect emerging cephalosporin resistance. Now that gonorrhea is largely diagnosed by a convenient DNA test, many laboratories and providers no longer have the capability of culturing N gonorrhoeae for drug resistance testing. The CDC is urging health departments to maintain or develop this capacity and to evaluate any gonorrhea treatment failures for possible resistance.
“Importantly, with fluoroquinolones no longer recommended, only one class of drugs remains recommended for treating gonorrhea: the antibiotics known as cephalosporins,” Dr. Douglas says. “Although the cephalosporins offer several potential options for treating gonorrhea, the lack of additional classes of antibiotics is a serious concern. There are currently no new drugs for gonorrhea in the drug development pipeline.”
To bolster international monitoring for the emergence of cephalosporin resistance, CDC is also working with the World Health Organization (WHO) and with government and industry partners to identify and evaluate new drug regimens for gonorrhea treatment.
“While we have not seen any evidence of resistance to cephalosporins to date, emergence of any resistance would be a serious public health concern,” Dr. Douglas said. “CDC will work with government and industry partners to identify and evaluate promising alternative drug regimens for treating gonorrhea. Ultimately, reducing the burden of gonorrhea will require comprehensive and continued action on many fronts, as we work to maintain and expand effective programs to prevent and control this disease across the nation.”
Most cases of gonorrhea in women are asymptomatic and untreated. However, failure to treat gonorrhea aggressively and early may result in pelvic inflammatory disease with associated infertility, chronic pelvic pain, and/or ectopic pregnancy. In men, rare complications of untreated gonorrhea may include epididymitis, rarely associated with infertility.
Even when asymptomatic, inflammation of the male genitourinary tract associated with gonorrhea may increase susceptibility to HIV infection. Rarely, untreated gonorrhea may be associated with serious sequelae such as infectious arthritis, meningitis or endocarditis.
Updated recommended treatment regimens for gonorrhea infection are as follows:
For uncomplicated gonococcal infections of the cervix, urethra, and rectum, recommended treatments are 125 mg of ceftriaxone in a single intramuscular (IM) dose or 400 mg of cefixime (not available in the United States) in a single oral dose, plus treatment of Chlamydia if chlamydial infection is not ruled out. Although 400-mg tablets of cefixime are not available in the United States, and it is only available in a suspension formulation, Dr. Douglas said that the CDC has approached the Food and Drug Administration regarding this, and they are hopeful that oral tablets will soon be an option in the United States.
“While we only have this single class of recommended antibiotics, the cephalosporins, and the vigilance we’ve talked about today is a key public health priority, we’ve been using this class of drugs for the treatment of gonorrhea since the early 1980s, and fortunately, so far, there has not been any documentation of emergence of resistance,” Dr. Douglas says. “I don’t want to present an injectable antibiotic as an insurmountable obstacle, because we used it for years with penicillin; it’s more of a bump in the road in terms of how providers will be caring for patients with gonorrhea.”
Alternative regimens for uncomplicated gonococcal infections of the cervix, urethra, and rectum are 2 g of spectinomycin (not available in the United States) in a single IM dose or cephalosporin single-dose regimens (ceftizoxime, 500 mg IM; or cefoxitin, 2 g IM, administered with probenecid, 1 g orally; or cefotaxime, 500 mg IM).
For uncomplicated gonococcal infections of the pharynx, recommended regimens are 125 mg of ceftriaxone in a single IM dose, plus treatment of Chlamydia if chlamydial infection is not ruled out. There are currently no recommended alternatives for pharyngeal infection.
For disseminated gonococcal infection, pelvic inflammatory disease, epididymitis, and treatment of gonorrheal infections in patients with documented severe allergic reactions to penicillins or cephalosporins, updated treatment regimens are available at http://www.cdc.gov/std/treatment.
A limitation of findings from GISP, which is conducted in publicly funded clinics and includes only male urethral isolates, is that they might not be representative of the entire US population infected with gonorrhea.
“We’ve looking hard for resistance for the duration of the GISP project, and we’ve never seen gonorrhea that we would consider to be resistant to cephalosporins,” Dr. Douglas said. “Based on global surveillance, we have not documented any strains resistant to cephalosporins at all. That’s comforting, of course, but because of the genetic versatility of the organism, it’s not something we feel completely complacent about.
Although test of cure is not recommended routinely for uncomplicated gonorrhea treated with recommended or alternative regimens, persons with persistent symptoms of gonococcal infection or whose symptoms recur shortly after treatment with a recommended or alternative regimen should be reevaluated by culture for N gonorrhoeae. Positive isolates should be tested for antimicrobial susceptibility, and clinicians and laboratories should report treatment failures or resistant gonococcal isolates to the CDC at the telephone number: 1-404-639-8373, through state and local public health authorities.
“In [other] Gram-negative bacteria, very highly resistant strains even to these third generation cephalosporin antibiotics have occurred,” Dr. Douglas concluded. “It’s just very hard to know if that could happen [for N gonorrheae], and when it could happen, but it’s certainly not implausible. Can it happen? Absolutely.”
Morbid Mortal Wkly Rep. 2007;56:332-336.